Nephrotoxicity of immunosuppressive drugs: experimental and clinical observations

Cyclosporine has improved patient and graft survival rates in solid organ transplantation since its introduction in 1976, and has been increasingly applied with considerable clinical benefit in the treatment of autoimmune diseases. However, the therapeutic benefits of immunosuppressive therapy for transplantation and autoimmune indications have been frequently limited by the occurrence of acute and chronic nephrotoxicity, which is the most obvious common side effect. Cyclosporine nephrotoxicity therefore remains an important clinical challenge. The clinical aspects and pathophysiology of nephrotoxicity induced by current and future immunosuppressive drugs are reviewed in this article, with an emphasis on the studies of chronic cyclosporine nephropathy, which is characterized by a decrease in glomerular filtration rate, afferent arteriolopathy, and striped tubulointerstitial fibrosis. Insights gained from experimental models of chronic nephrotoxicity associated with tubulointerstitial fibrosis and arteriolopathy are presented to elucidate the pathophysiology. Thus, experimental and clinical data regarding tacrolimus (FK506) and sirolimus (rapamycin) are presented.